The present invention is related to a novel process for preparing certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25, 1981].
These piperidine derivatives can be described by the following formulas: ##STR1## wherein R.sub.1 represents hydrogen or hydroxy;
R.sub.2 represents hydrogen; or PA1 R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ; PA1 n is an integer of from 1 to 5; PA1 R.sub.3 is --CH.sub.2 OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; PA1 each of A is hydrogen or hydroxy; and PA1 pharmaceutically acceptable salts, hydrates and individual optical isomers thereof. PA1 R.sub.2 represents hydrogen; or PA1 R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ; PA1 n is an integer of from 1 to 5; PA1 R.sub.3 is --CH.sub.2 OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; PA1 each of A is hydrogen or hydroxy; and PA1 pharmaceutically acceptable salts, hydrates and individual optical isomers thereof comprising the steps of: PA1 (a) reacting the .omega.-halo hydroxyethylphenylketone with a suitable reducing agent to produce a .omega.-halo hydroxyethylphenylalcohol; PA1 (b) reacting the .omega.-halo hydroxyethylphenylalcohol with a piperidine compound of the formula ##STR6## wherein R.sub.1 and R.sub.2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH; PA1 (c) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH; and PA1 (d) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl. PA1 (e) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl with an appropriate deprotecting reagent, PA1 (a) reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH with a suitable reducing agent to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH; PA1 (b) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH; and PA1 (c) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl. PA1 (d) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH, the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-c are optionally protected or unprotected.
The novel process for preparing the piperidine derivatives of formula (I) and formula (II) of the present invention offers high yields and ease of purification.